BR112016012747B1 - PROCESS FOR PREPARING A RACEMIC MIXTURE OF (RR,SS)-D6-TETRABENAZINE - Google Patents

Abstract

METHODS OF MANUFACTURING BENZOQUINOLINE COMPOUNDS The present invention relates to novel methods of manufacturing vesicular benzoquinoline inhibitors of monoamine transporter 2 (VMAT2) and its intermediates. Novel methods of making benzoquinoline compounds of Formula (I), including tetrabenazine analogues and deuterated tetrabenazine such as d6-tetrabenazine are described herein. Tetrabenazine is a vesicular inhibitor of monoamine transporter 2 (VMAT2) and is commonly prescribed for the treatment of Huntington's disease. D6-Tetrabenazine is a deuterated analogue of tetrabenazine that has improved pharmacokinetic properties compared to the non-deuterated drug and is currently in clinical development. (I)

Description

[001] This application claims the priority benefit of Interim Application US 61/911,214, filed December 3, 2013, the disclosure of which is incorporated herein by reference as if written herein in its entirety.

[002] Methods of manufacturing benzoquinoline compounds and their intermediates are described here.

[003] Tetrabenazine (Nitoman, Xenazine, Ro 1-9569), 1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinoline , is a vesicular inhibitor of monoamine transporter 2 (VMAT2). Tetrabenazine is commonly prescribed for the treatment of Huntington's disease (Savani et al., Neurology 2007, 68(10), 797; and Kenney et al., Expert Review of Neurotherapeutics 2006, 6(1), 7-17).

d6-Tetrabenazina[004] d6-Tetrabenazine is a deuterated analogue of tetrabenazine that has improved pharmacokinetic properties when compared to the non-deuterated drug and is currently under clinical development. US 8,524,733.

d6-Tetrabenazine

Kinetic effect of the deuterium isotope

[005] Tetrabenazine is a VMAT2 inhibitor. The carbon-hydrogen bonds of tetrabenazine contain a natural distribution of hydrogen isotopes, namely 1H or protium (approximately 99.9844%), 2H or deuterium (approximately 0.0156%) and 3H or tritium (in the range between approximately 0. 5 and 67 tritium atoms per 1018 protium atoms). Increased levels of deuterium incorporation may produce a detectable deuterium isotope kinetic (DKIE) effect that could affect the pharmacokinetic, pharmacological and/or toxicological profiles of tetrabenazine compared to tetrabenazine which has natural levels of deuterium.

[006] Based on the findings made in our laboratory as well as considering the literature, tetrabenazine is metabolized in humans into the isobutyl and methoxy groups. The current approach reduces metabolism at some or all of these sites. Limiting the production of these metabolites has the potential to lessen the danger of administering such drugs and may even allow for increased dosage and/or increased efficacy. All of these transformations can occur by polymorphically expressed enzymes, exacerbating the variety among patients. Yet, some disorders are best treated when the matter is medicated around the clock or for an extended period of time. For all the above reasons, a drug with a longer half-life can result in greater efficacy and cost savings. The various deuteration patterns can be used to (a) reduce or eliminate unwanted metabolites, (b) increase the half-life of the parent drug, (e) decrease the number of doses needed to achieve the desired effect, (d) decrease the amount of a dose necessary to achieve the desired effect, (e) increase the formation of active metabolites, if all are formed, (f) decrease the production of deleterious metabolites in specific tissues, and/or (g) create a drug more effective and/or safer drug for polypharmacy, whether the polypharmacy is intentional or not. The deuteration approach demonstrated the ability to slow tetrabenazine metabolism and to attenuate inter-patient variability.

[007] Novel methods of making benzoquinoline compounds including deuterated tetrabenazine analogues, such as d6-tetrabenazine, are described herein.

ou um sal do mesmo, compreendendo: uma etapa de reação de um composto de Fórmula II ou um sal do mesmo com um composto de Fórmula III:

na presença de uma base; em que: R7-R12 e R15 são selecionados independentemente a partir do grupo consistindo em hidrogênio e deutério; e Y1 é selecionado a partir do grupo consistindo em acetóxi, alcóxi, halogênio, haloalcóxi, perhaloalcóxi, heteroalcóxi e arilóxi, qualquer um dos quais podem ser opcionalmente substituídos.[008] In certain embodiments of the present invention, a process for preparing a compound of formula IV is described herein:

or a salt thereof, comprising: a step of reacting a compound of Formula II or a salt thereof with a compound of Formula III:

in the presence of a base; wherein: R7-R12 and R15 are independently selected from the group consisting of hydrogen and deuterium; and Y1 is selected from the group consisting of acetoxy, alkoxy, halogen, haloalkoxy, perhaloalkoxy, heteroalkoxy and aryloxy, any of which may be optionally substituted.

[009] In some embodiments, Y1 is acetoxy.

[0010] In some embodiments, Y1 is C1-C4 alkoxy.

[0011] In some embodiments, Y1 is ethoxy.

[0012] In some embodiments, Y1 is selected from the group consisting of fluorine, chlorine and bromine.

[0013] In some embodiments, said base is selected from the group consisting of alkali metal alkoxides, alkali metal hydroxides, alkali metal hydrides, alkali metal carbonates and trialkylamines.

[0014] In some embodiments, said base is an alkali metal alkoxide.

[0015] In some embodiments, said base is sodium tert-butoxide.

[0016] In some embodiments, Y1 is ethoxy.

compreendendo: uma etapa de reação de um composto de Fórmula IV ou um sal do mesmo com um composto de Fórmula V:

em um solvente e na presença de uma base; em que: R1-R12 e R15 são selecionados independentemente a partir do grupo consistindo em hidrogênio e deutério; e Y2 é selecionado a partir do grupo consistindo em halogênio, alquil sulfato, alquil sulfonato, halosulfonato, perhaloalquil sulfonato, aril sulfonato, alquilaril sulfonato, dialquiloxônio, alquilfosfato e alquilcarbonato, qualquer um dos quais podem ser opcionalmente substituídos.[0017] In certain embodiments of the present invention, a process for preparing a compound of formula VI is described herein:

comprising: a step of reacting a compound of Formula IV or a salt thereof with a compound of Formula V:

in a solvent and in the presence of a base; wherein: R1-R12 and R15 are independently selected from the group consisting of hydrogen and deuterium; and Y2 is selected from the group consisting of halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkylxonium, alkylphosphate and alkylcarbonate, any of which may be optionally substituted.

[0018] In some embodiments, Y2 is iodide or methyl sulfate.

[0019] In some embodiments, Y2 is iodide.

[0020] In some embodiments, said base is selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides, alkali metal hydroxides, alkali metal hydrides, and trialkylamines.

[0021] In some embodiments, said base is an alkali metal carbonate.

[0022] In some embodiments, said base is potassium carbonate.

[0023] In some embodiments, said solvent is selected from the group consisting of acetone, acetonitrile, dimethylformamide, 2-methyltetrahydrofuran and tetrahydrofuran.

[0024] In some embodiments, said solvent is acetone.

[0025] In some embodiments, the volume of said solvent is between about 5 to about 15 times the mass of the compound of formula IV.

[0026] In some embodiments, the volume of said solvent is between about 6 to about 10 times the mass of the compound of formula IV.

[0027] In some embodiments, the volume of said solvent is about 8 times the mass of the compound of formula IV.

[0028] In some embodiments, said reaction step is carried out in the presence of a phase transfer catalyst.

[0029] In some embodiments, said phase transfer catalyst is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium iodide and 18-crown-6.

[0030] In some embodiments, said phase transfer catalyst is tetrabutylammonium bromide.

compreendendo: uma primeira etapa de reação de um composto de Fórmula VI:

com um agente de desidratação em um solvente de reação; uma segunda etapa de adição de um solvente de têmpera e um anti-solvente à mistura reacional; e uma terceira etapa de isolamento do sal do composto de fórmula VII a partir da mistura de reação; em que: R1-R12 e R15 são selecionados independentemente a partir do grupo consistindo em hidrogênio e deutério.[0031] In certain embodiments of the present invention, a process for preparing a solid salt of the compound of formula VII is described herein:

comprising: a first step of reacting a compound of Formula VI:

with a dehydrating agent in a reaction solvent; a second step of adding a quenching solvent and an anti-solvent to the reaction mixture; and a third step of isolating the salt of the compound of formula VII from the reaction mixture; wherein: R1-R12 and R15 are independently selected from the group consisting of hydrogen and deuterium.

[0032] In some embodiments, said salt of the compound of formula I is the hydrochloride salt.

[0033] In some embodiments, said dehydrating agent is selected from the group consisting of phosphorus oxychloride, phosphorus pentachloride and thionyl chloride.

[0034] In certain embodiments, the amount of said phosphorus oxychloride is between about 0.5 to about 4 molar equivalents relative to the compound of formula VI.

[0035] In certain embodiments, the amount of said phosphorus oxychloride is between about 1.6 to about 2.0 molar equivalents relative to the compound of formula VI.

[0036] In certain embodiments, the amount of said phosphorus oxychloride is about 1.8 molar equivalents with respect to the compound of formula VI.

[0037] In certain embodiments, said reaction solvent is selected from the group consisting of tert-butyl methyl ether, toluene and acetonitrile.

[0038] In certain embodiments, said reaction solvent is acetonitrile.

[0039] In certain embodiments, the volume of said acetonitrile is between about 1 to about 4 times the mass of the compound of formula VI.

[0040] In certain embodiments, the volume of said acetonitrile is between about 1.5 to about 2.5 times the mass of the compound of formula VI.

[0041] In certain embodiments, the volume of said acetonitrile is about 2 times the mass of the compound of formula VI.

[0042] In certain embodiments, said quench solvent is an amprotic solvent selected from the group consisting of water, an alcohol and a protic acid.

[0043] In certain embodiments, said quench solvent is selected from the group consisting of ethanol, 1-propanol, isopropanol, 1-butanol, 2-methylpropanol, tert-butanol and 1-pentanol.

[0044] In certain embodiments, said quench solvent is 1-butanol.

[0045] In certain embodiments, the amount of said 1-butanol is between about 2 and about 8 molar equivalents relative to the compound of Formula VI.

[0046] In certain embodiments, the amount of said 1-butanol is between about 2.4 to about 6 molar equivalents relative to the compound of Formula VI.

[0047] In certain embodiments, the amount of said 1-butanol is between about 3.4 to about 4.2 molar equivalents relative to the compound of Formula VI.

[0048] In certain embodiments, the amount of said 1-butanol is about 3.8 molar equivalents relative to the compound of Formula VI.

[0049] In certain embodiments, said quench solvent is selected from the group consisting of hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid and trifluoroacetic.

[0050] In certain embodiments, said anti-solvent is selected from the group consisting of tert-butyl methyl ether, ethyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, diethyl ether, toluene, hexane, pentane and cyclo -hexane.

[0051] In certain embodiments, said anti-solvent is tert-butyl methyl ether.

[0052] In certain embodiments, the volume of said tert-butyl methyl ether is between about 1 to about 10 times the mass of the compound of Formula VI.

[0053] In certain embodiments, the volume of said tert-butyl methyl ether is between about 3 to about 5 times the mass of the compound of Formula VI.

[0054] In certain embodiments, the volume of said tert-butyl methyl ether is about 4 times the mass of the compound of Formula VI.

[0055] In certain embodiments, said first reaction step is carried out at reflux.

[0056] In certain embodiments, said first reaction step is maintained at a temperature of between about 0°C to about 100°C.

[0057] In certain embodiments, said first reaction step is maintained at a temperature of between about 75°C to about 95°C.

[0058] In certain embodiments, said first reaction step is maintained at a temperature of between about 80°C to about 85°C.

[0059] In certain embodiments, said first reaction step is maintained at a temperature of between about 80°C to about 85°C for about 2 hours.

[0060] In certain embodiments, after said first reaction step is heated to between about 80°C to about 85°C, the reaction mixture is cooled to a temperature between about 25°C to about 35°C. Ç.

[0061] In certain embodiments, said second reaction step is carried out between about 0°C to about 100°C.

[0062] In certain embodiments, said second reaction step is carried out between about 10°C to about 50°C.

[0063] In certain embodiments, said second reaction step is carried out between about 25°C to about 35°C.

[0064] In certain embodiments, the reaction mixture is maintained at a temperature between about 25°C to about 35°C for about 12 hours after the addition of said quench solvent and said anti-solvent.

[0065] In certain embodiments, said salt of the compound of formula VII is isolated by filtration.

compreendendo: uma primeira etapa de mistura do composto de Fórmula VII com um ou mais solventes; e uma segunda etapa de filtrar o sal do composto de fórmula VII a partir da mistura; em que: R1-R12 e R15 são selecionados independentemente a partir do grupo consistindo em hidrogênio e deutério.[0066] In certain embodiments, a process for purifying a hydrochloride salt of the compound of formula VII is described herein:

comprising: a first step of mixing the compound of Formula VII with one or more solvents; and a second step of filtering the salt of the compound of formula VII from the mixture; wherein: R1-R12 and R15 are independently selected from the group consisting of hydrogen and deuterium.

[0067] In certain embodiments, said solvent is selected from the group consisting of ethanol, 1-propanol, isopropanol, 2-methylpropanol, tert-butanol, 1-butanol, 1-pentanol, acetone, acetonitrile, acetate ethyl, tert-butyl methyl ether, hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid and trifluoroacetic acid.

[0068] In certain embodiments, said solvent is a mixture of ethanol and tert-butyl methyl ether.

[0069] In certain embodiments, said solvent is a mixture of 10% ethanol and 90% tert-butyl methyl ether.

[0070] In certain embodiments, said first mixing step is performed between about 0°C to about 60°C.

[0071] In certain embodiments, said first mixing step is performed between about 20°C to about 40°C.

[0072] In certain embodiments, said first mixing step is performed between about 28°C to about 32°C.

compreendendo: uma etapa de reação de um composto de Fórmula VII ou um sal do mesmo com um composto de Fórmula VIII em um ou mais solventes:

em que: R1-R27 são selecionados independentemente a partir do grupo consistindo em hidrogênio e deutério. X é selecionado a partir do grupo consistindo em halogênio, alquil sulfato, alquil sulfonato, halosulfonato, perhaloalquil sulfonato, aril sulfonato, alquilaril sulfonato, dialquiloxônio, alquilfosfato e alquilcarbonato, quaisquer um dos quais podem ser opcionalmente substituídos.[0073] In certain embodiments, a process for preparing a compound of formula IX is described herein:

comprising: a step of reacting a compound of Formula VII or a salt thereof with a compound of Formula VIII in one or more solvents:

wherein: R1-R27 are independently selected from the group consisting of hydrogen and deuterium. X is selected from the group consisting of halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkylxonium, alkylphosphate and alkylcarbonate, any of which may be optionally substituted.

[0074] In certain embodiments, said solvent is selected from the group consisting of water, methanol and ethanol.

[0075] In certain embodiments, said solvent is a mixture of methanol and water.

[0076] In certain embodiments, said mixture of methanol and water is between about five parts methanol to one part water and about one part methanol to one part water.

[0077] In certain embodiments, said mixture of methanol and water is between about four parts methanol to one part water and about two parts methanol to one part water.

[0078] In certain embodiments, said mixture of methanol and water is about three parts methanol to one part water.

[0079] In certain embodiments, the volume of said mixture of methanol and water is between about 2 and about 10 times the mass of the compound of Formula VII.

[0080] In certain embodiments, the volume of said mixture of methanol and water is between about 4 and about 8 times the mass of the compound of Formula VII.

[0081] In certain embodiments, the volume of said mixture of methanol and water is about 6 times the mass of the compound of Formula VII.

[0082] In certain embodiments, said solvent is a mixture of ethanol and water.

[0083] In certain embodiments, said mixture of ethanol and water is between about five parts ethanol to one part water and about one part ethanol to one part water.

[0084] In certain embodiments, said mixture of ethanol and water is between about four parts ethanol to one part water and about two parts ethanol to one part water.

[0085] In certain embodiments, said mixture of ethanol and water is about three parts ethanol to one part water.

[0086] In certain embodiments, the volume of said mixture of ethanol and water is between about 2 and about 10 times the mass of the compound of Formula VII.

[0087] In certain embodiments, the volume of said mixture of ethanol and water is between about 4 and about 8 times the mass of the compound of Formula VII.

[0088] In certain embodiments, the volume of said mixture of ethanol and water is about 6 times the mass of the compound of Formula VII.

[0089] In certain embodiments, said reaction step is carried out at a temperature of between about 0°C to about 100°C.

[0090] In certain embodiments, said reaction step is carried out at a temperature of between about 25°C to about 70°C.

[0091] In certain embodiments, said reaction step is carried out at a temperature of between about 40°C to about 60°C.

[0092] In certain embodiments, said reaction step is carried out at a temperature of between about 45°C to about 50°C.

[0093] In certain embodiments, said reaction step is carried out for about 1 to about 96 hours.

[0094] In certain embodiments, said reaction step is carried out for about 24 to about 72 hours.

[0095] In certain embodiments, said reaction step is carried out for about 48 hours.

[0096] In certain embodiments, wherein the compound of formula VII is the hydrochloride salt and a base is added during the reaction step.

[0097] In certain embodiments, said base is selected from the group consisting of alkali metal carbonates, alkali metal bicarbonates, alkali metal alkoxides, alkali metal hydroxides, alkali metal hydrides, and trialkylamines.

[0098] In certain embodiments, said base is an alkali metal carbonate.

[0099] In certain embodiments, said base is potassium carbonate.

compreendendo: uma primeira etapa de reação de um composto de Fórmula X ou um sal do mesmo com uma base em um ou mais solventes:

uma segunda etapa de ajuste do pH da mistura de reação pela adição de um ácido; uma terceira etapa de adição de dimetilamina ou um sal da mesma e um equivalente de formaldeído à mistura de reação; uma quarta etapa de reduzir o pH da mistura de reação pela adição de um ácido; uma quinta etapa de aumentar o pH da mistura de reação pela adição de uma base; uma sexta etapa de adição de dimetilamina ou um sal da mesma à mistura de reação; em que: R16-R27 são selecionados independentemente a partir do grupo consistindo em hidrogênio e deutério.[00100] In certain embodiments, a process for preparing a compound of formula XI is described herein:

comprising: a first step of reacting a compound of Formula X or a salt thereof with a base in one or more solvents:

a second step of adjusting the pH of the reaction mixture by the addition of an acid; a third step of adding dimethylamine or a salt thereof and an equivalent of formaldehyde to the reaction mixture; a fourth step of reducing the pH of the reaction mixture by the addition of an acid; a fifth step of increasing the pH of the reaction mixture by the addition of a base; a sixth step of adding dimethylamine or a salt thereof to the reaction mixture; wherein: R16-R27 are independently selected from the group consisting of hydrogen and deuterium.

[00101] In certain embodiments, the base used in the first hydrolysis step or the fifth pH adjustment step is selected from the group consisting of alkali metal carbonates and alkali metal hydroxides.

[00102] In certain embodiments, said base is an alkali metal hydroxide.

[00103] In certain embodiments, said base is potassium hydroxide.

[00104] In certain embodiments, said dimethylamine is dimethylamine hydrochloride.

[00105] In certain embodiments, said formaldehyde equivalent is selected from the group consisting of formaldehyde, aqueous formaldehyde solution, paraformaldehyde and trioxane.

[00106] In certain embodiments, said formaldehyde equivalent is an aqueous formaldehyde solution.

[00107] In certain embodiments, the acid used in the second pH adjustment step or the fourth pH adjustment step is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid.

[00108] In certain embodiments, said acid is hydrochloric acid.

[00109] In certain embodiments, a phase transfer catalyst is added during the third step of the reaction.

[00110] In certain embodiments, said phase transfer catalyst is tetrabutylammonium bromide.

[00111] In certain embodiments, the amount of said tetrabutylammonium bromide is about 0.1 molar equivalents relative to said compound of Formula X.

[00112] In certain embodiments, said solvent is water.

[00113] In certain embodiments, the first hydrolysis step is carried out by adding about 1 to about 2 molar equivalents of potassium hydroxide to said compound of Formula X.

[00114] In certain embodiments, the first hydrolysis step is carried out by adding from about 1 to about 1.2 molar equivalents of potassium hydroxide relative to said compound of Formula X.

[00115] In certain embodiments, the first hydrolysis step is carried out by adding about 1.1 molar equivalents of potassium hydroxide to said compound of Formula X.

[00116] In certain embodiments, the first hydrolysis step is carried out at a temperature of between about 0°C to about 100°C.

[00117] In certain embodiments, the first hydrolysis step is carried out at a temperature of between about 20°C to about 40°C.

[00118] In certain embodiments, the second pH adjustment step results in a pH of about 6 to about 8.

[00119] In certain embodiments, the second pH adjustment step results in a pH of about 6.8 to about 7.2.

[00120] In certain embodiments, the second pH adjustment step is performed at a temperature between about 10°C to about 60°C.

[00121] In certain embodiments, the third addition step is carried out by adding about 1 to about 2 molar equivalents of dimethylamine and equivalent of formaldehyde to said compound of Formula X.

[00122] In certain embodiments, the third addition step is performed by adding about 1.25 to about 1.75 molar equivalents of dimethylamine and about 1.25 to about 1.75 molar equivalents of of formaldehyde with respect to said compound of Formula X.

[00123] In certain embodiments, the third addition step is performed by adding about 1.5 molar equivalents of dimethylamine and about 1.68 molar equivalents of formaldehyde equivalent to said compound of Formula X.

[00124] In certain embodiments, the third addition step is carried out at a temperature between about 10°C to about 60°C.

[00125] In certain embodiments, the third addition step is carried out at a temperature of between about 25°C to about 35°C.

[00126] In certain embodiments, the reaction temperature is maintained for about 1 to about 24 hours after the third addition step.

[00127] In certain embodiments, the reaction temperature is maintained for about 9 to about 15 hours after the third addition step.

[00128] In certain embodiments, the reaction temperature is maintained for about 12 hours after the third addition step.

[00129] In certain embodiments, the fourth pH adjustment step results in a pH less than 3.

[00130] In certain embodiments, the fourth pH adjustment step results in a pH less than 1.

[00131] In certain embodiments, the fourth pH adjustment step is performed at a temperature between about 10°C to about 60°C.

[00132] In certain embodiments, the fourth pH adjustment step is performed at a temperature of between about 25°C to about 35°C.

[00133] In certain embodiments, the fifth pH adjustment step results in a pH greater than 10.

[00134] In certain embodiments, the fifth pH adjustment step results in a pH of about 12 to about 13.

[00135] In certain embodiments, the fifth pH adjustment step is performed at a temperature between about 10°C to about 60°C.

[00136] In certain embodiments, the fifth pH adjustment step is performed at a temperature of between about 25°C to about 35°C.

[00137] In certain embodiments, the sixth addition step is carried out by adding from about 1 to about 2 molar equivalents of dimethylamine to said compound of Formula X.

[00138] In certain embodiments, the sixth addition step is carried out by adding from about 1.25 to about 1.75 molar equivalents of dimethylamine to said compound of Formula X.

[00139] In certain embodiments, the sixth addition step is carried out by adding about 1.5 molar equivalents of dimethylamine to said compound of Formula X.

[00140] In certain embodiments, the sixth addition step is carried out at a temperature between about 10°C to about 60°C.

[00141] In certain embodiments, the sixth addition step is carried out at a temperature of between about 25°C to about 35°C.

[00142] In certain embodiments, the reaction temperature is maintained for about 1 to about 96 hours after the third addition step.

[00143] In certain embodiments, the reaction temperature is maintained for about 24 to about 48 hours after the third addition step.

[00144] In certain embodiments, the reaction temperature is maintained for about 36 hours after the third addition step.

[00145] Compounds as described herein may also contain less prevalent isotopes for other elements, including, but not limited to, 13C or 14C for carbon, 33S, 34S, or 36S for sulfur, 15N for nitrogen, and 17O or 18O for oxygen.

[00146] All publications and references cited herein are expressly incorporated herein by reference in their entirety. However, with respect to any similar or identical terms found in both publications or incorporated references and those explicitly extended or defined in this document, then the definitions or meanings of those terms explicitly extended in this document shall control in all respects.

[00147] As used herein, the following terms have the meanings indicated.

[00148] The singular forms "a", "a" and "the" may refer to articles in the plural unless otherwise indicated.

[00149] The term "about" as used herein is intended to qualify numerical values that change, denoting a value such as variable within a margin of error. When any particular margin of error, such as a standard deviation from a significant value determined on a graph or table of data, is recited, the term "about" should be understood to mean that the range which would encompass the recited value and the range that would include by rounding up or down that number also takes into account significant figures.

[00150] When ranges of values are described, and the notation "from n1 ... to n2" or "n1-n2" is used, where n1 and n2 are the numbers, then unless otherwise specified In this way, this notation is intended to include the numbers themselves and the range between them. This range can be integral or continuous between and include the final values.

[00151] The term "deuterium enrichment" refers to the percentage of incorporation of deuterium at a given position in a molecule in place of hydrogen. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the naturally occurring distribution of deuterium is about 0.0156%, the enrichment of deuterium at any position in a compound synthesized using unenriched starting materials is about 0.0156%. Deuterium enrichment can be determined using conventional analytical methods known to one skilled in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[00152] The term "is/are deuterium" when used to describe a particular position in a molecule, such as R1-R27 or the symbol "D", when used to represent a given position in a drawing of a molecular structure, means that the specified position is enriched with deuterium above the natural deuterium distribution. In one embodiment, the deuterium enrichment is not less than about 1%, in another not less than about 5%, in another not less than about 10%, in another not less than about 10%. 20%, in another not less than about 50%, in another not less than about 70%, in another not less than about 80%, in another not less than about 90%, or in another not less than about 98% deuterium at the specified position.

[00153] The term "isotopic enrichment" refers to the percentage of incorporation of a less common isotope of an element at a given position in a molecule at the location of the element's most prevalent isotope.

[00154] The term "non-isotopically enriched" refers to a molecule in which the percentages of the different isotopes are substantially the same naturally occurring percentages.

[00155] There are asymmetric centers in the compounds described herein. These centers are designated by the symbols "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. It is to be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as D-isomers and L-isomers and mixtures thereof. The individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials that contain chiral centers or by preparing mixtures of enantiomeric products followed by separation such as conversion of a mixture of diastereoisomers followed by separation or recrystallization, chromatographic techniques , direct separation of enantiomers on chiral chromatographic columns or any other suitable method known in the prior art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Furthermore, compounds described herein may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E) and zusammen (Z) as well as appropriate mixtures thereof. Furthermore, compounds can exist as tautomers; all tautomeric isomers are provided by this invention. Furthermore, the compounds described herein may exist in unsolvated forms as well as in forms solvated with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolved forms.

[00156] The terms "3S,1lbS enantiomer" or the term "3R,11bR enantiomer" refers to any of the stereo isomers of d6-tetrabenazine that have the following structural formulas:

[00157] In certain embodiments, a chemical structure may be drawn as either the 3S,11bS enantiomer or the 3R,11bR enantiomer, but the text of the report may indicate that the 3S,11bS enantiomer, the 3R,11bR enantiomer, a racemic mixture thereof (which may be described as (RR, SS)-d6-tetrabenazine), or all of the above may be intended to be described.

[00158] The terms "(3S,11bS)-enantiomer" or "(3R, 11bR)-enantiomer" or as applied to a compound of formula I refers to any of the stereo isomers of compounds of formula I shown below:

[00159] The term "bond" refers to a covalent bond between two atoms or two moieties when the atoms joined by the bond are considered to be part of the larger substructure. A bond can be single, double or triple unless otherwise stated. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position.

[00160] The term "alkoxy", as used herein, alone or in combination, refers to an alkyl ether radical, where the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n -propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

[00161] The term "alkyl" as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, said alkyl will comprise from 1 to 10 carbon atoms. In other embodiments, said alkyl will comprise from 1 to 6 carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term "alkylene" as used herein, alone or in combination, refers to a saturated aliphatic group derived from a saturated straight or branched hydrocarbon chain bonded to two or more positions, such as methylene (-CH 2 -) . Unless otherwise specified, the term "alkyl" may include "alkylene" groups.

[00162] The term "alkylamino" as used herein, alone or in combination, refers to an alkyl group affixed to the parent molecular moiety through an amino group. Suitable alkylamino groups may be monoor dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino and the like.

[00163] The term "amino" as used herein, alone or in combination, refers to -NRR', wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl , cycloalkyl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Furthermore, R and R' may combine to form heterocycloalkyl, each of which may be optionally substituted.

[00164] The term "aryl", as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together. The term "aryl" includes aromatic groups such as phenyl, naphthyl, anthracenyl and phenanthryl.

[00165] The term "halo" or "halogen" as used herein, alone or in combination, refers to fluorine, chlorine, bromine or iodine.

[00166] The term "haloalkoxy", as used herein, alone or in combination, refers to a haloalkyl group affixed to the parent molecular moiety through an oxygen atom.

[00167] The term "haloalkyl", as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are substituted with a halogen. Monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals are specifically encompassed. A monohaloalkyl radical, for one example, may have an iodine, bromine, chlorine or fluorine atom within the radical. Dihalo and polyhaloalkyl radicals can have two or more of the same halogen atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group bonded to two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-) and the like.

[00168] The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms are replaced by halogen atoms.

[00169] The term "perhaloalkyl", as used herein, alone or in combination, refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[00170] The terms "sulfonate", "sulfonic acid" and "sulfonic" as used herein, alone or in combination, refer to the -SO3H group and its anion or the -SO3- group.

[00171] The terms "sulfate," "sulfuric acid," and "sulfuric," as used herein, alone or in combination, refer to the group HOS(=0)2OH and its monoor di-anions or the group -S04-.

[00172] The terms "phosphate", "phosphoric acid" and "phosphoric acid" as used herein, alone or in combination, refer to the group P(=O)(OH)3 and its mono, di or tri- anions or the -PO4- group.

[00173] The term "carbonate" as used herein, alone or in combination, refers to the group -OC(=O)O-.

[00174] The term "VMAT2" refers to vesicular monoamine transporter 2, an integral membrane protein that acts to transport monoamines - particularly neurotransmitters such as dopamine, norepinephrine, serotonin and histamine - from the cytosol cell to synaptic vesicles.

[00175] The term "VMAT2-mediated disorder" refers to a disorder that is characterized by abnormal VMAT2 activity. A VMAT2-mediated disorder may be completely or partially mediated by VMAT2 modulation. In particular, a VMAT2-mediated disorder is one in which inhibition of VMAT2 results in some effect on the underlying disease, for example, administration of a VMAT2 inhibitor results in some improvement in at least some of the patients being treated.

[00176] The term "VMAT2 inhibitor", "VMAT2 inhibit", or "VMAT2 inhibition" refers to the ability of a compound described herein to alter VMAT2 function. A VMAT2 inhibitor can block or reduce VMAT2 activity by forming an irreversible or reversible covalent bond between the inhibitor and VMAT2 or by forming a non-covalently bound complex. Such inhibition may be manifested only in certain cell types or may be contingent on a particular biological event. The term "VMAT2 inhibitor", "inhibit VMAT2" or "inhibition of VMAT2" also refers to altering the function of VMAT2 by decreasing the likelihood of a complex forming between VMAT2 and a natural substrate.

[00177] VMAT2-mediated disorders include, but are not limited to, chronic hyperkinetic movement disorders, which can be psychogenic (eg, tics), idiopathic (eg, Tourette's syndrome and Parkinson's disease), genetic (as, for example, the chorea characteristic of Huntington's disease), infectious (as, for example, Sydenham's chorea), or drug-induced, as in tardive dyskinesia. Unless otherwise noted, "chronic hyperkinetic movement disorders" refers to and includes all movement disorders: psychogenic, idiopathic, genetic, and drug-induced. VMAT2 disorders also include disorders such as oppositional defiant disorder.

[00178] The compounds described herein may exist as therapeutically acceptable salts. The term "therapeutically acceptable salt", as used herein, represents salts or zwitterionic forms of the compounds described herein that are therapeutically acceptable, as defined herein. Salts can be prepared during the final isolation and purification of the compounds or separately by appropriately reacting the compound with a suitable acid or base. Therapeutically acceptable include acid and base addition salts. For a more complete discussion of salt preparation and selection, see the "Handbook of Pharmaceutical Salts, Properties and Use", Stah and Wermuth, Ed., (Wiley-VCH and VHCA, Zurich, 2002) and Berge et al., J .Pharm. Sci. 1977, 66, 1-19.

[00179] Suitable acids for use in preparing pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid , D-glucuronic acid, L-glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid , lactobionic acid, lauric acid, ma acid leiic, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid , nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino salicylic acid, sebacic acid, stearic acid , succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid and valeric acid.

[00180] Bases suitable for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide or sodium hydroxide; and organic bases such as primary, secondary, tertiary and quaternary, aliphatic and aromatic amines, including L-arginine, benetamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol , ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methylglucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-( 2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol and tromethamine.

[00181] While it may be possible for the compounds of the present invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions which comprise one or more of certain compounds described herein, or one or more pharmaceutically acceptable salts, prodrugs or solvates thereof, together with one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients. The appropriate formulation is dependent on the chosen route of administration. Any of the well known techniques, vehicles and excipients can be used as appropriate and as understood in the prior art; for example, in Remington's Pharmaceutical Sciences. The compositions described herein may be manufactured in any manner known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compression processes. Pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed, extended, extended, sustained, pulsatile, controlled, accelerated and rapid, scheduled, scheduled release and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (See, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc., New York, NY, 2002; Vol. 126).

General synthetic methods for preparing the compounds

[00182] Isotopic hydrogen can be introduced into a compound as described herein by synthetic techniques employing deuterated reagents, where incorporation rates are predetermined; and/or by exchange techniques, where incorporation rates are determined by equilibrium conditions and can be highly variable, depending on reaction conditions. Synthesis techniques, in which tritium or deuterium is directly and specifically inserted by tritiated or deuterated reagents of known isotopic content, can produce tritium or deuterium in high abundance, but may be limited by the chemistry required. Exchange techniques, on the other hand, can produce tritium or lower deuterium incorporation, often with the isotope being distributed over many sites on the molecule.

[00183] Compounds as described herein may be prepared by methods known to one skilled in the art and routine modifications thereof, and/or by processes similar to those described in the Examples section herein and routine modifications thereof, and/or procedures found in WO 2005077946 ; WO 2008/058261 ; EP 1716145; Lee et al., J. Med. Chem., 1996, (39), 191-196; Kilbourn et al., Chirality, 1997, (9), 59-62; Boldt et al., Synth. Commun., 2009, (39), 3574-3585; Rishel et al., J. Org. Chem., 2009, (74), 4001-4004; DaSilva et al., Appl. Radiation Isot., 1993, 44(4), 673-676; Popp et al., J. Pharm. Sci., 1978, 67(6), 871-873; Ivanov et al., Heterocycles 2001, 55(8), 1569-1572; US 2,830,993; US 3,045,021; WO 2007130365 ; WO 2008058261, which are incorporated herein in their entirety, and the references cited therein and routine modifications thereof. Compounds as described herein may also be prepared as shown in any of the following schemes and routine modifications thereof.

Esquema 1[00184] The following schemes may be used to practice the present invention. Any position shown as hydrogen can optionally be substituted with deuterium.

scheme 1

[00185] Compound 1 is reacted with compound 2, wherein Y1 is as defined in paragraph [0008], in the presence of a suitable basic catalyst, such as sodium tert-butoxide, at an elevated temperature to give compound 3 Compound 3 is reacted with Compound 4 in the presence of an appropriate base, such as potassium carbonate, in an appropriate solvent, such as acetone, to obtain Compound 5. Compound 5 is reacted with an appropriate dehydrating agent, such as phosphorus oxychloride, in a suitable solvent, such as acetonitrile, at an elevated temperature to give compound 6. Compound 7 is reacted with a suitable methylating agent, such as methyl iodide, in a suitable solvent, such as tert-butyl methyl ether at an elevated temperature to give compound 8. Compound 6 is reacted with compound 8, in the presence of an appropriate base, such as potassium carbonate, in a suitable solvent, such as a mixture of methanol and water at a temperature to give compound 9 of Formula 1. Compound 9 may optionally be purified by recrystallization from an appropriate solvent such as ethanol.

[00186] Deuterium can be incorporated at different positions synthetically, according to synthetic procedures, as shown in Scheme 1, through the proper use of deuterated intermediates. For example, for the introduction of deuterium at one or more positions of R7-R12, compound 1 with the corresponding deuterium substitutions can be used. To introduce deuterium into R15, compound 2 with the corresponding deuterium substitution can be used. To introduce deuterium at one or more positions of R1-R6, compound 4 with the deuterium substitutions is used. To introduce deuterium R16-R29, compound 7 with the corresponding ones can be used.

Esquema 2[00187] Deuterium, also various positions that have an exchangeable proton, via proton-deuterium equilibrium exchange.

scheme 2

[00188] Compound 10 is reacted with compound 11 in the presence of an appropriate base such as potassium carbonate, an optional alkylation catalyst such as potassium iodide, and an optional phase transfer catalyst such as bromide of tetrabutylammonium, in an appropriate solvent, such as dimethylformamide, at an elevated temperature to give compound 12. Compound 12 is reacted with an appropriate base, such as potassium hydroxide, in an appropriate solvent, such as water, to provide a carboxylic acid intermediate, which is further reacted with an appropriate secondary amine or salt thereof, such as dimethylamine hydrochloride, and a suitable formaldehyde equivalent, such as aqueous formaldehyde solution, in the presence of an appropriate acid, such as hydrochloric acid , and an optional phase transfer catalyst, such as tetrabutylammonium bromide, to obtain a mixture of compound 7 and compound 13. The mixture of compound 7 and compound 13 is further reacted with an appropriate secondary amine or salt thereof, such as dimethylamine hydrochloride, in the presence of an appropriate base, such as potassium hydroxide, in an appropriate solvent, such as water, to give compound 7 .

[00189] Deuterium can be incorporated at different positions synthetically, according to synthetic procedures, as shown in Scheme 1, through the proper use of deuterated intermediates. For example, for the introduction of deuterium at one or more positions of R16-R18, compound 10 with the corresponding deuterium substitutions can be used. To introduce deuterium at one or more positions of R19-R27, compound 11 with the corresponding deuterium substitutions can be used.

[00190] Deuterium can also be incorporated into various positions that have an exchangeable proton, via proton-deuterium equilibrium exchange.

N-(2-(3,4-dihidroxi-fenil)-etil)-formamida Etapa 1

[00191] The invention is further illustrated by the following examples. All IUPAC names were generated using “CambridgeSoft's ChemDraw 13.0”.EXAMPLE 1

N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide Step 1

Optimization of reaction conditions

[00192] General Procedure: Dopamine hydrochloride is suspended in ethyl formate at 25-30°C. The suspension is cooled to 10-15°C and sodium tert-butoxide is added in portions, maintaining the same temperature. The reaction mixture is heated at 50-55°C for 12 hours. After the reaction is complete, ethanol is added to the reaction mass and the temperature is maintained for 2 hours. The reaction mass is filtered and washed with 2 volumes of ethanol. The filtrate is concentrated in vacuo and water (0.5 volumes) is added to the residue and stirred for 1 hour at 25-30°C. The solid is filtered and washed with water (0.25 volume) and dried in a hot air oven at 55-60°C for 8 hours. Table 1: Optimization of reaction conditions by different equivalents of sodium tert-butoxide

Representative example - Step 1

Cloridrato de d6—6,7-dimetoxi-3,4-dihidroisoquinolina Etapa 1

[00193] N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide:Dopamine hydrochloride (250.0 g, 1.323 mol, 1.0 eq) was suspended in ethyl formate (2.5 L, 10.0 vol) at 25-30°C. The suspension was cooled to 10-15°C and sodium tert-butoxide (202 g, 2.12 mol, 1.60 eq) was added in portions, maintaining the same temperature. The reaction mixture was heated at 55-60°C for 12 hours and then concentrated under reduced pressure. To the remaining residue, water (125 mL, 0.5 vol) was added and stirred for 15 minutes. Volatile organic solvents were removed by vacuum distillation after the product precipitated. The suspension was cooled to 25-30°C and purified water (500 mL, 2.0 vol) was added. The solid was filtered and washed with water (125 mL, 0.5 vol) and dried in an oven at 55-60°C for 8 hours to obtain the title compound as a brown powder (203 g, yield = 84, 5%). 1H NMR (300 MHz, CDCl3), δ 8.72 (s, band, 2H), 7.96 (s, 1H), 6.548-6.630 (dd, 2H, J=8.1), 6.407-6.441 (d , 1H, J=2.1), 3.169-3.237 (q, 2H, J=6.9), 2.485-2.535 (t, 2H, J=7.8); LC-MS: m/z = 181.92 (MH)+. EXAMPLE 2

d6-6,7-Dimethoxy-3,4-dihydroisoquinoline hydrochloride Step 1

Optimization of reaction conditions

Tabela 3: Otimização das condições de reação por variação do volume de solvent

Tabela 4: Otimização das condições de reação por variação dos equivalentes molares de iodeto de metila

Tabela 5: Otimização das condições de reação por variação da temperatura de reação

Tabela 6: Otimização das condições de reação por variação do catalisador de transferência de fase e equivalentes de iodeto de metila

Tabela 7: Otimização das condições de reação por variação do catalisador de transferência de fase

Tabela 8: Otimização das condições de reação por variação da quantidade de catalisador de transferência de fase

[00194] General Procedure: N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide is loaded with solvent, base, phase transfer catalyst, if any, and dβ-methyl iodide (CD3I) at 25-30°C. The reaction temperature is adjusted and maintained for the specified time. The reaction is filtered, the filtrate distilled under reduced pressure, and the crude product partitioned between dichloromethane (6.0 vol) and water (4.0 vol). The layers are separated and the organic layer is washed twice with 3% aqueous NaOH solution (2x4.0 vol), followed by water (4.0 vol). The organic layer is distilled under reduced pressure to give crude d6-N-(2-(3,4-dimethoxy-phenyl)ethyl)-formamide. Table 2: Optimization of reaction conditions by varying the solvent

Table 3: Optimization of reaction conditions by varying the volume of solvent

Table 4: Optimization of reaction conditions by variation of molar equivalents of methyl iodide

Table 5: Optimization of reaction conditions by reaction temperature variation

Table 6: Optimization of reaction conditions by varying the phase transfer catalyst and methyl iodide equivalents

Table 7: Optimization of reaction conditions by varying the phase transfer catalyst

Table 8: Optimization of reaction conditions by varying the amount of phase transfer catalyst

Representative example - Step 1

[00195] d6-N-(2-(3,4-dimethoxy-phenyl)ethyl)formamide: N-(2-(3,4-dihydroxyphenyl)ethyl)formamide (190 g, 1.049 mol, 1.00 eq) was charged with acetone (1.52 L, 8.0 vol), followed by K2CO3 (434 g, 3.149 mol, 3.00 eq) at 25-30°C.CD3I (334 g, 2.309 mol, 2.20 eq ) was added to the reaction mixture over 1 hour at 25-30°C. The reaction temperature was maintained for 36 hours at 25-35°C. The reaction was filtered, the filtrate distilled under reduced pressure, and the crude product partitioned between dichloromethane (1.14 L, 6.0 vol) and water (760 mL, 4.0 vol). The layers were separated and the organic layer was washed twice with 3% aqueous NaOH solution (2x760 ml, 2x4.0 vol) followed by water (760 ml, 4.0 vol). The organic layer was distilled under reduced pressure to give 158g of crude d6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide. step 2

Optimization of reaction conditions

Tabela 10: Otimização das condições de reação por variação do solvente de têmpera e do anti-solvente (solvente da reação: tolueno)

Tabela 11: Otimização das condições de reação por variação do solvente de têmpera e do anti-solvente (solvente da reação: acetonitrila)

Tabela 12: Otimização das condições de reação por variação do anti-solvente(solvente da reação: acetonitrila, solvente de têmpera: 1-butanol)

Tabela 13: Otimização das condições de reação por variação dos equivalentes de 1-butanol (solvente da reação: acetonitrila, solvente de têmpera: 1-butanol)

Tabela 14: Otimização das condições de reação usando éter metil terc-butílico como solvente de reação e variando o solvente de tempera

Tabela 15: Otimização das condições de reação pela variação dos equivalentes de POCl3 usados

[00196] General Procedure: N-(2-(3,4-dimethoxy-phenyl)-ethyl)formamide is charged with a solvent and POCl 3 at 1015°C. The mixture is heated at an elevated temperature for 1 or 2 hours and then cooled to room temperature, after which a quenching solvent (e.g. a protic solvent such as an alcohol) is added and the mixture is stirred for 1 hour, followed by addition of an anti-solvent, if applicable. In some cases, d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride precipitates as a salt directly from the reaction mixture. In others, d6-6,7-dimethoxy-3,4-dihydroisoquinoline is isolated after acid-base processing.Table 9: Optimization of reaction conditions by varying the solvent

Table 10: Optimization of reaction conditions by varying the quenching solvent and anti-solvent (reaction solvent: toluene)

Table 11: Optimization of reaction conditions by varying the quenching solvent and anti-solvent (reaction solvent: acetonitrile)

Table 12: Optimization of reaction conditions by varying the anti-solvent (reaction solvent: acetonitrile, quenching solvent: 1-butanol)

Table 13: Optimization of the reaction conditions by varying the 1-butanol equivalents (reaction solvent: acetonitrile, quenching solvent: 1-butanol)

Table 14: Optimization of reaction conditions using tert-butyl methyl ether as reaction solvent and varying the tempering solvent

Table 15: Optimization of reaction conditions by varying the POCl3 equivalents used

Representative example - Step 2

[00197] d6-6,7-Dimethoxy-3,4-dihydroisoquinoline hydrochloride: To the crude d6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide from step 1 (158 g, 0.734 mol, 1.00 eq), acetonitrile (316 mL, 2.0 vol) was added followed by POCl 3 (202 g, 1.322 mol, 1.80 eq) at 10-15°C. The reaction mixture was heated at reflux for 2 hours and then cooled to 25-35°C. The temperature was maintained for 12 hours, after which it was quenched with n-butanol (255 mL, 2.79 mol, 3.8 eq) and tert-butyl methyl ether (1.26 L, 8.0 vol). The precipitated product was filtered, washed with ethyl acetate (632 mL, 4.0 vol), and dried under vacuum. The crude product was further purified by suspension in 10% ethanol in MTBE (944 ml, 8.0 vol) after which an orange-brown product (108 g, yield = 44.0%) was obtained after drying. 1H NMR (300 MHz, CDCl 3 ) δ 14.456 (br s, 1H), 9.105-9.133 (d, 1H, J = 8.4), 7.497 (s, 1H), 6.806 (s, 1H), 3.951-4.000 ( t, 2H, J = 7.5), 3.0893.144 (t, 2H, J = 8.4); LC-MS: m/z = 198.06 (MH+).

Step 3: Optional purification of de-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride

Tabela 17: Recristalização e lavagem do cloridrato de d6-6,7-dimetoxi-3,4-dihidroisoquinolina

EXEMPLO 3

(RR,SS)-1,3,4,6,7-11b-Hexaidro-9,10-di(metoxi-d3) -3- (2-metilpropil)-2H-benzo[a]quinolizin-2-ona((+/-)-d6- Tetrabenazina) Etapa 1

[00198] To increase the purity of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride various purification procedures were tested. Table 16: Recrystallization of de-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride

Table 17: Recrystallization and washing of d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride

EXAMPLE 3

(RR,SS)-1,3,4,6,7-11b-Hexahydro-9,10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one ((+/-)-d6- Tetrabenazine) Step 1

Representative example - Step 1

[00199] 2-Acetyl-N,N,N,4-Tetramethyl-1-pentanamonium Iodide: 3-[(dimethylamino)methyl]-5-methylhexan-2-one (90 g, 0.526 mol, 1, 00 eq) was charged with tert-butyl methyl ether (1.35 L, 15.0 vol) and cooled to 0-10°C. Methyl iodide (171 g, 1.209 mol, 2.3 eq) was slowly added to the reaction mixture and stirred for 15 hours at 25-35°C. The reaction was heated at 35-40°C for 2 hours. The precipitated solid was filtered under nitrogen and washed with tert-butyl methyl ether (900 mL, 10.0 vol). The crude product was further purified in a slurry of ethyl acetate (1.46 L, 10 vol) and filtered to give 2-acetyl-N,N,N,4-tetramethyl-1-pentanamonium iodide (146 g) as a white solid.

Optimization of reaction conditions

*A impureza de diastereoisômero é o diastereoisômero (RS,SR) da d6- tetrabenazina Tabelas 19 e 20 - Resultados do HPLC em processo

*MP= Material de partida - [6,7-Dimetoxi-3,4-dihidroisoquinolina]; A impureza de diastereoisômero é o diastereoisômero (RS,SR) da d6- tetrabenazina.

*MP= Material de partida - [6,7-Dimetoxi-3,4-dihidroisoquinolina]; A impureza de diastereoisômero é o diastereoisômero (RS,SR) da d6- tetrabenazina. Tabela 21: Otimização das condições de reação pela variação da temperatura de reação

*A impureza de diastereoisômero é o diastereoisômero (RS,SR) da d6- tetrabenazina Tabelas 22 e 23 - Resultados do HPLC em processo

*MP= Material de partida - [6,7-Dimetoxi-3,4-dihidroisoquinolina]; A impureza de diastereoisômero é o diastereoisômero (RS,SR) da d6- tetrabenazina.

*MP= Material de partida - [6,7-Dimetoxi-3,4-dihidroisoquinolina]; EA= acetato de etila; A impureza de diastereoisômero é o diastereoisômero (RS,SR) da d6-tetrabenazina. Tabela 24: Otimização das condições de reação pela variação da proporção do solvente da mistura

Tabelas 25 e 26 - Resultados do HPLC em processo

*MP= Material de partida - [6,7-Dimetoxi-3,4-dihidroisoquinolina]; EA= acetato de etila; A impureza de diastereoisômero é o diastereoisômero (RS,SR) da d6-tetrabenazina.

*MP= Material de partida - [6,7-Dimetoxi-3,4-dihidroisoquinolina]; EA=acetato de etila; A impureza de diastereoisômero é o diastereoisômero (RS,SR) da d6-tetrabenazina. Tabela 27: Otimização das condições de reação pela variação do tempo de reação

Tabelas 28 e 29 - Resultados do HPLC em processo

*MP= Material de partida - [6,7-Dimetoxi-3,4-dihidroisoquinolina]; EA=acetato de etila; A impureza de diastereoisômero é o diastereoisômero (RS,SR) da d6-tetrabenazina.

*MP= Material de partida - [6,7-Dimetoxi-3,4-dihidroisoquinolina]; EA= acetato de etila; A impureza de diastereoisômero é o diastereoisômero (RS,SR) da d6-tetrabenazina. Tabela 30: Comparação entre o cloridrato de do-6,7- dimetoxi-3,4-dihidroisoquinolina e o cloridrato de de—6,7- dimetoxi-3,4- dihidroisoquinolina

Tabela 31: Otimização pela variação da pureza do cloridrato de 6,7-dimetoxi-3,4-dihidroisoquinolina

[00200] General procedure: 2-acetyl-N,N,N,4-tetramethyl-1-pentanamonium iodide is charged to a suspension comprising d6-6,7-dimethoxy-3,4-dihydroisoquinoline (hydrochloride or free base, 1.00 eq) and solvent. If d6-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride is used, a base is added to the reaction mixture at room temperature. The reaction mixture is stirred at an appropriate temperature, cooled and water is added. The reaction mass is filtered and the solids are washed with water and dried to give the title compound. (The diastereoisomer (RR,SS) of d6-tetrabenazine is the desired product). Table 18: Optimization of reaction conditions by varying the solvent

*The diastereoisomer impurity is the diastereoisomer (RS,SR) of d6-tetrabenazine Tables 19 and 20 - In-process HPLC results

*MP= Starting material - [6,7-Dimethoxy-3,4-dihydroisoquinoline]; The diastereoisomer impurity is the diastereoisomer (RS,SR) of d6-tetrabenazine.

*MP= Starting material - [6,7-Dimethoxy-3,4-dihydroisoquinoline]; The diastereoisomer impurity is the diastereoisomer (RS,SR) of d6-tetrabenazine. Table 21: Optimization of reaction conditions by varying the reaction temperature

*The diastereoisomer impurity is the diastereoisomer (RS,SR) of d6-tetrabenazine Tables 22 and 23 - In-process HPLC results

*MP= Starting material - [6,7-Dimethoxy-3,4-dihydroisoquinoline]; The diastereoisomer impurity is the diastereoisomer (RS,SR) of d6-tetrabenazine.

*MP= Starting material - [6,7-Dimethoxy-3,4-dihydroisoquinoline]; EA=ethyl acetate; The diastereoisomer impurity is the diastereoisomer (RS,SR) of d6-tetrabenazine. Table 24: Optimization of reaction conditions by varying the proportion of solvent in the mixture

Tables 25 and 26 - HPLC results in process

*MP= Starting material - [6,7-Dimethoxy-3,4-dihydroisoquinoline]; EA=ethyl acetate; The diastereoisomer impurity is the diastereoisomer (RS,SR) of d6-tetrabenazine.

*MP= Starting material - [6,7-Dimethoxy-3,4-dihydroisoquinoline]; EA=ethyl acetate; The diastereoisomer impurity is the diastereoisomer (RS,SR) of d6-tetrabenazine. Table 27: Optimization of reaction conditions by reaction time variation

Tables 28 and 29 - Results of HPLC in process

*MP= Starting material - [6,7-Dimethoxy-3,4-dihydroisoquinoline]; EA=ethyl acetate; The diastereoisomer impurity is the diastereoisomer (RS,SR) of d6-tetrabenazine.

*MP= Starting material - [6,7-Dimethoxy-3,4-dihydroisoquinoline]; EA=ethyl acetate; The diastereoisomer impurity is the diastereoisomer (RS,SR) of d6-tetrabenazine. Table 30: Comparison between do-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride and de-6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride

Table 31: Optimization by varying the purity of 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride

Claims (14)

1. Process for preparing a racemic mixture of (RR,SS)-d6-tetrabenazine:

(RR,SS)-d6-tetrabenazine in which the deuterium enrichment of (RR,SS)-d6-tetrabenazine is not less than 10%, CHARACTERIZED by the fact that it comprises: reacting d6-6,7-dimethoxy-3, 4-dihydroisoquinoline, or a salt thereof:

d6-6,7-dimethoxy-3,4-dihydroisoquinoline with a 2-acetyl-N,N,N,4-tetramethyl-1-pentanamonium salt

wherein X is halogen, alkyl sulfate, alkyl sulfonate, halosulfonate, perhaloalkyl sulfonate, aryl sulfonate, alkylaryl sulfonate, dialkylxonium, alkylphosphate or alkylcarbonate; and an optional base; in the presence of a solvent mixture which is a combination of water and an alcohol which is methanol or ethanol, wherein the alcohol to water ratio is between 5:1 and 1:1; at a temperature of about 40°C to about 60°C; for a period of time sufficient to produce (RR,SS)-d6-tetrabenazine having a diastereomeric purity of at least 99%, based on high performance liquid chromatography. Process, according to claim 1, CHARACTERIZED in that the solvent mixture is a mixture of methanol and water. Process according to claim 2, CHARACTERIZED in that the methanol:water ratio is between 5:1 and 2:1. Process according to claim 1, CHARACTERIZED in that d6-6,7-dimethoxy-3,4-dihydroisoquinoline is a salt form of d6-6,7-dimethoxy-3,4-dihydroisoquinoline which is d6 hydrochloride -6,7-dimethoxy-3,4-dihydroisoquinoline. Process according to claim 4, CHARACTERIZED in that the process is carried out in the presence of a base. 6. Process, according to claim 1, CHARACTERIZED in that X is halogen. Process according to claim 1, CHARACTERIZED in that the time period is from 24 hours to 63 hours. Process, according to claim 1, CHARACTERIZED in that the temperature is from 40°C to 60°C. Process according to claim 1, CHARACTERIZED in that the temperature is from 45°C to 50°C. Process according to claim 1, CHARACTERIZED in that the diastereomeric purity is at least 99.1%. Process according to claim 4, CHARACTERIZED in that it further comprises obtaining d6-6,7-dimethoxy-3,4-dihydroisoquinoline HCl in a process comprising: a. react dopamine HCl:

with ethyl formate, in the presence of a base, to obtain N-(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide

B. further, reacting -(2-(3,4-dihydroxy-phenyl)-ethyl)-formamide with d3-methyl iodide (Cd3l), in the presence of a solvent and a base to obtain d6-N-(2-(3, 4-dimethoxy-phenyl)-ethyl)-formamide.

ç. further, reacting d6-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-formamide with a dehydrating agent in a reaction solvent to obtain d6-6,7-dimethoxy-3,4-dihydroisoquinoline HCl. Process according to claim CHARACTERIZED in that the deuterium enrichment of (RR,SS) tetrabenazine is not less than 50%. Process according to claim CHARACTERIZED in that the deuterium enrichment of (RR,SS) tetrabenazine is not less than 90%. Process according to claim CHARACTERIZED in that the deuterium enrichment of (RR,SS) tetrabenazine is not less than 98%.